Early events in sepsis-associated cholestasis.
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Chemokines, CC↗
Biomedical subjects
M Müller
Publications and source records attributed to M Müller.
Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.
BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patients with normal gamma-glutamyltransferase activity have mutations of the FIC1 locus on chromosome 18q21 or mutations of the BSEP gene on chromosome 2q24. Also, patients with bile acid synthesis defects have low gamma-glutamyltransferase activity. We investigated expression of the bile salt export pump (BSEP) in liver samples from patients with a PFIC phenotype and correlated this with BSEP gene mutations. METHODS: BSEP and multidrug resistance protein 2 (MRP2) expressions were studied by immunohistochemistry in liver specimens of 28 patients and BSEP gene mutation analysis in 19 patients. Bile salt kinetics were studied in 1 patient. RESULTS: Sixteen of 28 liver samples showed no canalicular BSEP staining. Staining for MRP2 showed a normal canalicular pattern in all but 1 of these samples. Ten of 19 patients showed BSEP gene mutations; BSEP protein expression was lacking in all 10 patients. No mutations were found in 9 of 19 patients, and in all except 1, BSEP protein expression was normal. Bile salt concentration in bile of BSEP-negative/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of normal) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of normal). The kinetic study confirmed the dramatic decrease of bile salt secretion in BSEP-negative patients. CONCLUSIONS: The findings show a close correlation between BSEP gene mutations and canalicular BSEP expression. Biliary secretion of bile salts is greatly reduced in BSEP-negative patients.
ATP Binding Cassette Transporter, Subfamily B↗
Localization of the Wilson's disease protein in human liver.
BACKGROUND & AIMS: Wilson's disease is an autosomal-recessive disorder of copper metabolism that results from the absence or dysfunction of a copper-transporting P-type adenosine triphosphatase that leads to impaired biliary copper excretion and disturbed holoceruloplasmin synthesis. To gain further insight into the role of the Wilson's disease protein in hepatic copper handling, its localization in human liver was investigated. METHODS: By use of a specific antibody, localization of the Wilson's disease protein was studied in liver membrane fractions and liver sections by immunoblotting, immunohistochemistry, and double-label confocal scanning laser microscopy. RESULTS: The 165-kilodalton protein, found by immunoblotting, was most abundant mainly in isolated plasma membrane fractions enriched in canalicular domains. Immunohistochemistry revealed intracellular punctuate staining of hepatocytes in certain regions of the liver, whereas a canalicular membrane staining pattern was observed in other regions. Double-labeling studies showed that in the latter regions the transporter is present mainly in vesicular structures just underneath the canalicular membrane that are positive for markers of the trans-Golgi network. A weak staining of the canalicular membrane, identified by staining for P-glycoprotein, was observed. CONCLUSIONS: These results show that in human liver the Wilson's disease protein is predominantly present in trans-Golgi vesicles in the pericanalicular area, whereas relatively small amounts of the protein appear to localize to the canalicular membrane, consistent with a dual function of the protein in holoceruloplasmin synthesis and biliary copper excretion.
Adenosine Triphosphatases↗
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats.
BACKGROUND & AIMS: Biliary cholesterol secretion is coupled to that of phospholipids in a process controlled by mdr2 P-glycoprotein activity and bile salt secretion. Statins, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been shown to affect hepatobiliary lipid secretion in rats. The aim of this study was to relate the effects of statins on bile formation to the expression of mdr2 and other hepatic adenosine triphosphate-dependent transport proteins involved in bile formation in rats. METHODS: Rats received simvastatin- or pravastatin-containing chow continuously for 5 days. In one group of rats, simvastatin treatment was withdrawn 9-12 hours before the end of the experiment to induce biliary cholesterol hypersecretion (rebound). Bile and liver tissue were collected for lipid analysis, and hepatic messenger RNA (mRNA) and protein levels were studied by reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS: Simvastatin feeding did not alter biliary bile salt secretion. Secretion of phospholipids and cholesterol was stimulated by 74% and 90%, respectively, in the simvastatin-continuous group and by 72% and 235%, respectively, in the rebound group compared with controls. mdr2 mRNA levels increased only in the continuous group. mdr2 protein levels increased in both simvastatin-fed groups. Induction was most pronounced in periportal hepatocytes. mdr1b mRNA levels were moderately increased in both simvastatin-fed groups. Levels of other hepatic transport proteins did not change. Similar results were obtained in pravastatin-fed rats. CONCLUSIONS: Statins increase expression of mdr2 and mdr1b in rats, revealing a novel effect of these commonly used drugs.
ATP Binding Cassette Transporter, Subfamily B↗
Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria.
BACKGROUND & AIMS: Reduced activity of ferrochelatase in erythropoietic protoporphyria (EPP) results in protoporphyrin (PP) accumulation in erythrocytes and liver. Liver disease may occur in patients with EPP, some of whom develop progressive liver failure that necessitates transplantation. We investigated the mechanisms underlying EPP-associated liver disease in a mouse model of EPP. METHODS: Liver histology, indicators of lipid peroxidation, plasma parameters of liver function, and bile composition were studied in mice homozygous (fch/fch) for a point mutation in the ferrochelatase gene and in heterozygous (fch/+) and wild-type (+/+) mice. RESULTS: Microscopic examination showed bile duct proliferation and biliary fibrosis with portoportal bridging in fch/fch mice. PP content was 130-fold increased, and thiobarbituric acid-reactive substances (+30%) and conjugated dienes (+75%) were slightly higher in fch/fch than in fch/+ and +/+ livers. Levels of hepatic thiols (-12%) and iron (-52%) were reduced in fch/fch livers. Liver enzymes and plasma bilirubin were markedly increased in the homozygotes. Plasma bile salt levels were 80 times higher in fch/fch than in fch/+ and +/+ mice, probably related to the absence of the Na(+)-taurocholate cotransporting protein (Ntcp) in fch/fch liver. Paradoxically, bile flow was not impaired and biliary bile salt secretion was 4 times higher in fch/fch mice than in controls. Up-regulation of the intestinal Na(+)-dependent bile salt transport system in fch/fch mice may enhance efficiency of bile salt reabsorption. The bile salt/lipid ratio and PP content of fch/fch bile were increased 2-fold and 85-fold, respectively, compared with +/+, whereas biliary glutathione was reduced by 90%. Similar effects on bile formation were caused by griseofulvin-induced inhibition of ferrochelatase activity in control mice. CONCLUSIONS: Bile formation is strongly affected in mice with impaired ferrochelatase activity. Rather than peroxidative processes, formation of cytotoxic bile with high concentrations of bile salts and PP may cause biliary fibrosis in fch/fch mice by damaging bile duct epithelium.
Animals↗
Evaluation and application of models for the prediction of ready biodegradability in the MITI-I test.
Three existing models and one newly developed model for the prediction of ready biodegradability of organic compounds are evaluated by comparing the descriptors they use, and the consistency of the models when applied to the set of High Production Volume Chemicals (HPVC) in the European Union. Linear regression models developed for the OECD showed the best performance in the external validation (84.7% correct), although comparison with the other three models is flawed because of the class specificity of these models. With these models 567 of the 894 compounds could be predicted in the validation. The multivariate statistical model showed the best performance in the external validation (82.7% correct) combined with the broadest applicability of the model. The evaluation of the predictions of the models for the HPVC shows that all models are highly consistent in their prediction of not-ready biodegradability, but much less consistency is seen in the prediction of ready biodegradability. This complies with the observation that all 4 models show better performance in their predictions of not-ready biodegradability.
Analysis of Variance↗
Influence of polyglactin-coating on functional and morphological parameters of polypropylene-mesh modifications for abdominal wall repair.
Regarding oversized mechanical properties of most of the currently available materials a new mesh was developed (ETHICON, Norderstedt, Germany) and exactly adopted to the physiology of the human abdominal wall by reducing the amount of polypropylene (weight of <30 g/m2; mesh A). The consecutive increase of pores size as well as the use of multifilaments led to a pronounced increase of flexibility. To improve the handling during operation the initial stiffness of this low-weight large pores mesh was increased by strengthening with different amounts of absorbable polyglactin (combination of glycolide and lactide) in various forms: by coating (mesh B), adding multifilament polyglactin filaments (mesh C, Vypro) or both (mesh D), respectively. To test the consequences of the different supplementary techniques all mesh variants are implanted in a rat model. Over implantation intervals of 3, 7, 14, 21 and 90 days we measured the tensile strength, the resulting stiffness and surveyed the tissue response, particularly in regard to the extent of inflammation and to the induced fibrosis. The results proved a sufficient mechanical stability of the material reduced and pure polypropylene mesh A without restriction of the mobility of the abdominal wall compared with a group that had simple laparotomy and closure. The histological analysis of the interface showed a minor inflammatory reaction and a dense vascularisation. The addition of polyglactin multifilaments (mesh C) reduces the number of macrophages and granulocytes as indicators for acute inflammation, showing generally a scar formation limited merely to the perifilamentary region. The abdominal wall compliance remained unchanged compared with mesh A. The coating of the polypropylene with polyglactin (mesh B and D) appeared to change the tissue reaction remarkably, favouring the formation of a connective tissue capsule around the whole mesh. The mechanical testing revealed an apparent protrusion with an increase of curvature of the artificial abdominal wall at rising intraabdominal pressures. The entire coating of the polypropylene surface with polyglactin induces an all embedding scar plate, filling out the pores and forming a tissue capsule. The complex interaction of tissue and implanted biomaterials with their distinct alterations of the tissue response confirms the necessity of in vivo experiments even after 'minor' modifications. Whereas the addition of polyglactin filaments appears to be favourable, the coating of polypropylene with polyglactin seems to hinder the incorporation of the mesh.
Abdominal Muscles↗
Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids: a study in isolated hepatocyte couplets and TR- rats.
BACKGROUND/AIMS: Fluorescent bile acids have proved useful for characterizing bile salt transport mechanisms. The aim of this study was to further validate the use of lysyl-fluorescein conjugated bile acid analogues as surrogate bile acids. METHODS: We analyzed biliary excretion kinetics of cholyl lysyl fluorescein (CLF), lithocholyl lysyl fluorescein (LLF) and sulfo-lithocholyl lysyl fluorescein (sLLF), both in the isolated rat hepatocyte couplet model and in TR- rats with a selective canalicular transport defect of non-bile acid organic anions. RESULTS: CLF and LLF, which like their natural nonsulfated bile acid congeners are expected to be handled by the canalicular bile salt export pump, were transferred into the bile canaliculus much faster than sLLF, a putative substrate for the canalicular multispecific organic anion transporter in both the in vivo and the in vitro models employed. The contention that different transport systems are involved in sulfated and non-sulfated lysyl fluorescein conjugated bile acids biliary excretion was supported further by studies using TR- rats, in which the cumulative biliary excretion of sLLF was reduced to 6% as compared with that of normal Wistar rats, in good agreement with values for its naturally-occurring radiolabeled parent compound sulfoglycolithocholate. In contrast, CLF and LLF were reduced to 66% and 52%, similar values to these for their congeners, [14C] glycocholate and [14C] lithocholate. CONCLUSION: The close similarity in behavior of lysyl fluorescein conjugated bile acids to that of their naturally-occurring parent compounds in these different models gives support for both sulfated and nonsulfated lysyl fluorescein conjugated bile acids as substitute molecules for studies of bile acid transport.
Animals↗
The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems.
Natural polyamines, spermidine and spermine, and their precursor putrescine, are of considerable importance for the developing and mature nervous system. They exhibit a number of neurophysiological and metabolic effects in the nervous system, including control of nucleic acid and protein synthesis, modulation of ionic channels and calcium-dependent transmitter release. The polyamine system is also known to be involved in various brain pathologic events (seizures, stroke, Alzheimer's disease and others). While cerebral polyamine concentrations and the activities of polyamine-metabolizing enzymes have been studied in great detail, much less is known about the cells that are responsible for cerebral polyamine synthesis and interconversion. With the present review the attempt is made to show how exact knowledge about the regional distribution and cellular localization of polyamines and the polyamine-synthesizing enzymatic machinery (and especially of L-ornithine decarboxylase) may help to better understand the functional interplay between polyamines and other endogenous agents (transmitters, receptors, growth factors neuroactive drugs etc.). Polyamines have been localized both in neurones and glial cells. However, the main cellular locus of the ODC is the neuron--both in the immature and adult central nervous system. Each period of normal brain development and ageing seems to have its own, characteristic temporo-spatial pattern of neuronal ODC expression. During strong functional activation (kindling, epileptic seizures, neural transplantation) astrocytes and other non-neuronal cells do also express ODC and other polyamine-metabolizing enzymes. Astroglial expression of ODC is accompanied by an increase in glial fibrillary acidic protein in these cells. This shift in the cellular mechanisms of polyamine metabolism is currently far from being understood. In human brain diseases (Alzheimer's disease, schizophrenia) certain neurones show an increased expression of ODC, the first and rate-limiting enzyme of polyamine metabolism. Since polyamines are structurally related to psychoactive drugs (neuroleptics, antidepressants) the polyamine system might be of importance as a putative target for drug intervention in psychiatry.
Animals↗
Responses of auditory nerve fibers innervating regenerated hair cells after local application of gentamicin at the round window of the cochlea in the pigeon.
Hair cells in the basilar papilla of birds have the capacity to regenerate after injury. There is also functional recovery of hearing after regeneration of the hair cells. The present study was undertaken to determine the effect of local aminoglycoside application on the physiology of auditory nerve fibers innervating regenerated hair cells. Collagen sponges loaded with gentamicin were placed at the round window of the cochlea in adult pigeons. The local application of gentamicin-loaded collagen sponges resulted in total hair cell loss over at least the basal 62% of the basilar papilla. According to the pigeon cochlear place-frequency map (Smolders, Ding-Pfennigdorff and Klinke, Hear. Res. 92 (1995) 151-169), frequencies above 0.3 kHz are represented in this area. Physiological data on single auditory nerve fibers were obtained 14 weeks after gentamicin treatment. The response properties showed the following characteristics when compared to control data: CF thresholds (CF = characteristic frequency) were elevated in units with CF above 0.15 kHz, sharpness of tuning (Q10dB) was reduced in units with CF above 0.38 kHz, low-frequency slopes of the tuning curves were reduced in units with CF above 0.25 kHz, high frequency slopes of the tuning curves were reduced in units with CF above 0.4 kHz, spontaneous firing rate was reduced in units with CF above 0.38 kHz, dynamic range of rate-intensity functions at CF was reduced in units with CF above 0.4 kHz and the slopes of these rate-intensity functions were elevated in units with CF above 0.4 kHz. Maximum discharge rate was the only parameter that remained unchanged in regenerated ears. The results show that the response properties of auditory nerve fibers which innervate areas of the papilla that were previously devoid of hair cells are poorer than the controls, but that action potential generation in the afferent fibers is unaffected. This suggests that despite structural regeneration of the basilar papilla, functional recovery of the auditory periphery is incomplete at the level of the hair cell or the hair cell-afferent synapse.
Administration, Topical↗
Different techniques of distal aortic repair in acute type A dissection: impact on late aortic morphology and reoperation.
OBJECTIVE: To compare three different techniques of distal aortic repair in acute type A (de Bakey type I) aortic dissection and to evaluate their impact on the late morphology of the aortic arch and descending aorta and on the incidence of reoperation. METHODS: From 65 patients operated on due to an acute type A aortic dissection between 1989 and 1993, 54 long-term survivors underwent clinical and radiologic follow-up examination after a mean postoperative interval of 62+/-16 months. The surgical techniques of distal aortic reconstruction included closed repair using Teflon felt reinforcement under moderate hypothermic cardiopulmonary bypass (n = 20) and open repair in deep hypothermic circulatory arrest using either Teflon felt reinforcement (n = 16) or gelatin-resorcin-formaldehyde (GRF) glue (n = 18) to readapt the dissected aortic layers. In all patients, MR imaging was performed on a 1.5-T whole body imaging system for the evaluation of the morphology and function of the heart, aorta and supraaortic branches. RESULTS: Overall hospital mortality following surgical repair of type A aortic dissection was 15.4% during this time period. The highest rate of persistent false lumen perfusion (17/20, 85%) and presence of an intimal flap in the aortic arch (13/20, 65%) was observed in patients following closed repair of acute ascending aortic dissection, whereas the lowest rate of such findings was demonstrated in patients who had undergone open distal aortic repair using biological glue (false lumen perfusion 10/18, 55% and intimal flap in the arch 2/18, 11%). Redo-surgery was significantly reduced in the open repair group using GRF glue (1/18, 5.5%) as compared with the Teflon felt repair group (3/16, 18%) and the closed repair group (6/20, 30%). CONCLUSIONS: In patients with acute type A dissection, open distal aortic repair using GRF-glue favourably influences both (1) the severity of late morphologic alterations in the downstream aorta and (2) the incidence of reoperation.
Aortic Dissection↗
Prolonged bleeding after cardiopulmonary bypass with recombinant hirudin in heart transplantation.
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Blood Component Transfusion↗
Per aspera ad protozoa et astra, Yuri I. Polyansky and Russian protistology.
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Animals↗
Stable long-term germ-line transmission of transgene integration sites in mice.
Transgenic mice provide a valuable tool in all fields of basic and applied biological and medical research. In this study, we describe the fate of integrated transgenes in the mammalian host genome over a large number of generations. The stability of the germ-line transmission of integrated tyrosinase transgene copies was monitored up to generation F20 in a large number of individuals from seven transgenic mouse lines. Phenotypic and molecular genetic analysis of the offspring both within the different lines and in cross-breeding experiments revealed the high stability of the transgene integration sites in mice. Only very few individuals were affected by a transgene copy loss. These results indicate that, once homozygous transgenic lines are established, breeding programs can be continued to a high number of generations without further stringent molecular genetic analysis.
Animals↗
Cerebrovascular resistance and blood flow velocity changes after carotid endarterectomy.
BACKGROUND: To study the pattern of cerebral blood flow velocity and cerebral resistance changes after carotid endarterectomy. PATIENTS AND METHODS: In 81 patients (mean age +/- SD, 64 +/- 8 years) with unilateral carotid endarterectomy (CEA) the systolic, diastolic and mean blood velocities, and the pulsatility index (PI) were recorded in both middle cerebral arteries preoperatively and repetitively postoperatively with the use of transcranial Doppler ultrasound (TCD). RESULTS: In the middle cerebral artery ipsilateral to CEA mean blood velocity was increased 6 hours (64 +/- 25 cm/sec; p < 0.005) and 7 days (54 +/- 15 cm/sec; p < 0.05) after CEA and had returned to the preoperative level (49 +/- 11 cm/sec) after 3 months. Compared to preoperatively (0.86 +/- 22), the PI was significantly increased at 6 hours examination (1.03 +/- 23, p < 0.005), and remained increased thereafter. A pathologically increased mean blood velocity (> 83 cm/sec) 6 hours after CEA occurred in 11 patients, two of them developed a slight hyperperfusion syndrome. In the contralateral middle cerebral artery, only the diastolic blood velocity showed significant changes (preoperatively, 35 +/- 12 cm/sec; 3 months after CEA, 33 +/- 8 cm/sec; p < 0.05). CONCLUSIONS: Using TCD, hemodynamic changes occur predominantly in the middle cerebral arteries ipsilateral to CEA. Early postoperative TCD studies may be of help to identify patients at risk to develop a hyperperfusion syndrome.
Aged↗
Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cells in vivo is resolved by differentiation into type I cells and by apoptosis.
Keratinocyte growth factor (KGF) is a potent mitogen of alveolar epithelial type II cells (AEII). AEII hyperplasia is resolved within several days following intratracheal instillation of KGF by unknown mechanism(s). AEII hyperplasia was induced in rat lungs by intrabronchial instillation of 5 mg recombinant human (rh)KGF x kg body weight(-1) or an equivalent amount of diluent. Epithelial architecture, cell proliferation, transformation of AEII into type I cells (AEI) and apoptosis were investigated by means of immunohistochemistry, stereology, double immunofluorescence microscopy, electron microscopy and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) technique in lungs fixed 1, 2, 3 and 7 days after treatment. After 1 day of rhKGF instillation, an increase was observed in the nuclear antigen Ki-67, a proliferation marker detected by the antibody MIB-5-expressing surfactant protein (SP)-B, -C, -D-positive AEII. The incidence of mitosis was increased by day 2, resulting in AEII micropapillae with intense basolateral expression of the exon 6 containing isoform (v6) of CD446 (CD44v6), a marker for AEII. By day 3, monolayers of AEII exhibiting lateral CD44v6 covered 45% of the alveolar surface. After 7 days, there were numerous intermediate AEII/AEI cells characterized by a flat elongated shape, staining for SP-D, apical appearance of AEI marker Lycopersicon esculentum lectin and lateral staining for AEII marker CD44v6. Increased numbers of TUNEL-positive epithelial cells were seen at days 2-7. In conclusion, restoration of normal alveolar epithelium after instillation of recombinant human keratinocyte growth factor is accomplished by terminal differentiation and apoptosis of hyperplastic alveolar epithelial type II cells in vivo.
Animals↗
ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1.
The present study was performed to investigate the ability of the multidrug resistance protein (MRPI) to transport different cationic substrates in comparison with MDR1-P-glycoprotein (MDR1). Transport studies were performed with isolated membrane vesicles from in vitro selected multidrug resistant cell lines overexpressing MDR1 (A2780AD) or MRP1 (GLC4/Adr) and a MRP1-transfected cell line (S1(MRP)). As substrates we used 3H-labelled derivatives of the hydrophilic monoquaternary cation N-(4',4'-azo-in-pentyl)-21-deoxy-ajmalinium (APDA), the basic drug vincristine and the more hydrophobic basic drug daunorubicin. All three are known MDR1-substrates. MRP1 did not mediate transport of these substrates per se. In the presence of reduced glutathione (GSH), there was an ATP-dependent uptake of vincristine and daunorubicin, but not of APDA, into GLC4/Adr and S1(MRP) membrane vesicles which could be inhibited by the MRP1-inhibitor MK571. ATP- and GSH-dependent transport of daunorubicin and vincristine into GLC4/Adr membrane vesicles was inhibited by the MRP1-specific monoclonal antibody QCRL-3. MRP1-mediated daunorubicin transport rates were dependent on the concentration of GSH and were maximal at concentrations > or = 10 mM. The apparent KM value for GSH was 2.7 mM. Transport of daunorubicin in the presence of 10 mM GSH was inhibited by MK571 with an IC50 of 0.4 microM. In conclusion, these results demonstrate that MRP1 transports vincristine and daunorubicin in an ATP- and GSH-dependent manner. APDA is not a substrate for MRP1.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1.
1. The intracellular transport of leukotriene C4 (LTC4) in hematopoietic cells such as human monocytes is controlled by an ATP dependent carrier encoded by the multidrug resistance protein1 (MRPI) gene whose function can be blocked by the compound MK-571. Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRPI mediated function by MK-571 might affect cytokine production. 2. MK-571 strongly enhanced IL-6 expression at mRNA and protein level in lipopolysaccharide (LPS) and interleukin-1 (IL-1) stimulated human monocytes giving rise to 2.0+/-0.4 (x+/-s.d.) and 5.7+/-3.5 fold induction of IL-6 protein secretion. The increase in IL-6 secretion was accompanied by an enhanced phosphorylation of p38 but not of c-Jun-N terminal kinase. 3. The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 signalling route. MK-571 mediated upregulation of IL-6 in the presence of IL-1 was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK-571 did not affect the IL-1 induced DNA binding activity of Activator Protein-1 and Nuclear Factor-kappaB but rather enhanced the transactivational activity of an IL-6 promoter construct. Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC). 4. These results indicate that the membrane transporter MRP1 is involved in the regulation of IL-6 expression in activated human peripheral blood monocytes.
ATP-Binding Cassette Transporters↗